Abstract:

The present invention is directed to devices, systems, and methods for
monitoring inhaled drug usage to predict when an acute attack or
exacerbation of a disease, such as a respiratory disease, is imminent.
Instrumented inhalers that use modular designs with standard components
are disclosed, as are systems for monitoring the instrumented inhalers.
Also disclosed are methods for determining whether or not a patient's
inhaled drug usage pattern indicates that an acute attack or disease
exacerbation is imminent, and notifying appropriate medical personnel of
any usage patterns indicative of an attack or disease exacerbation. If
such an attack or exacerbation is imminent, additional therapeutic agents
may be dispensed to the patient or other interventions made.

Claims:

1-20. (canceled)

21. A metered dose inhaler, comprising:a) an inhaler portion including:i)
a medication reservoir compartment constructed and adapted to engage a
medication reservoir or to contain medication;ii) a mouthpiece; andiii) a
flow pathway opening into and connecting the medication reservoir
compartment and the mouthpiece so as to deliver a metered dose of a
medication from the medication reservoir compartment to the mouthpiece
when the inhaler portion is actuated to dispense a metered dose of the
medication; andb) a sensor/transmitter portion including:i) a
dose-dispensing sensor positioned external to the inhaler portion, the
dose-dispensing sensor being coupled to the inhaler portion such that
when the inhaler portion is actuated to dispense the dose of the
medication, the dose-dispensing sensor establishes a signal in response
thereto; andii) a wireless transmitter connected to the dose-dispensing
sensor, the wireless transmitter being constructed and arranged to accept
the signal from the dose-dispensing sensor and transmit a signal
indicating that a dose has been dispensed to a remote station.

22. The metered dose inhaler of claim 21, wherein the inhaler portion
further comprises a movable part constructed and arranged to move
between: (1) a dispensing position in which the inhaler portion is
actuated to dispense a dose of the medication; and (2) a non-dispensing
position in which medication does not flow from the medication reservoir
compartment into the mouthpiece, the movable part being biased toward the
non-dispensing position.

23. The metered dose inhaler of claim 21, further comprising a coupling
element connected to the movable part, the coupling element being
constructed and arranged to couple the dose-dispensing sensor to the
movement of the movable part such that the dose-dispensing sensor is
activated when the movable part moves into the dispensing position.

24. The metered dose inhaler of claim 23, wherein a medication reservoir
installed in the medication reservoir compartment serves as the movable
part.

25. The metered dose inhaler of claim 24, wherein the dose-dispensing
sensor comprises a mechanical pressure switch that is activated when
depressed.

26. The metered dose inhaler of claim 25, wherein the coupling element
comprises a cap or lip secured to the medication reservoir such that the
cap or lip will contact and depress the dose-dispensing sensor when the
medication reservoir is in the depressed, dispensing position.

28. The metered dose inhaler of claim 21, further comprising a
microprocessor connected between the dose-dispensing sensor and the
wireless transmitter.

29. The metered dose inhaler of claim 28, wherein:a) the microprocessor
controls the wireless transmitter to transmit the signal indicating that
the dose has been dispensed at a predetermined interval of time after the
dose has been dispensed; andb) the signal indicating that the dose has
been dispensed comprises the amount of the dose or number of times that
the inhaler portion was actuated, and the time that the dose was
dispensed.

31. The metered dose inhaler of claim 21, wherein the sensor/transmitter
portion is releasably secured to the inhaler portion.

32. A system for predicting disease exacerbations based on inhaled drug
usage patterns, comprising:a) one or more inhalers, each of the one or
more inhalers being adapted to dispense a dose of a first therapeutic
agent to a patient, and to transmit information regarding the dispensing
of the dose wirelessly; andb) a monitoring system in communication with
the one or more inhalers, the monitoring system being operable to record
and associate the information from the one or more inhalers with patient
records;wherein:1) either or both of the one or more inhalers and the
monitoring system are adapted to analyze the information to determine
whether the inhaled drug usage patterns established by the information
are exacerbation patterns indicative of an imminent disease exacerbation;
and2) the monitoring system is adapted to notify medical personnel of
patient conditions, including any exacerbation patterns.

33. A method for predicting disease exacerbations based on inhaled drug
usage patterns, comprising:a) collecting data on usage of a first inhaled
therapeutic agent by a patient essentially in real time as doses of the
first inhaled therapeutic agent are dispensed;b) analyzing the data to
determine whether an exacerbation pattern indicative of an imminent
disease exacerbation exists; andc) notifying medical personnel of any
exacerbation pattern.

34. The method of claim 33, wherein the first inhaled therapeutic agent is
a short acting bronchodilator.

35. The method of claim 34, wherein the short acting bronchodilator is
selected from the group consisting of albuterol; bitolterol mesylate;
levalbuterol; metaproterenol sulfate; pirbuterol acetate; and terbutaline
sulfate.

36. The method of claim 33, further comprising causing or allowing a
patient to receive a second therapeutic agent if the analysis indicates
an exacerbation pattern.

38. The method of claim 33, wherein an exacerbation pattern comprises one
or more conditions selected from the group consisting of:a) increased
usage of the first inhaled therapeutic agent;b) nocturnal usage of the
first inhaled therapeutic agent; andc) increased frequency of use of the
first therapeutic agent.

39. The method of claim 33, further comprising notifying the patient of
any exacerbation patterns.

40. The method of claim 33, wherein said method is performed using
machine-readable instructions on a machine-readable medium interoperable
with one or more machines.

Description:

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001]The present application claims priority to, and the benefit of, U.S.
Provisional Patent Application No. 60/899,404, filed on Feb. 5, 2007, the
contents of which are incorporated by reference herein in their entirety.

FIELD OF THE INVENTION

[0003]The present invention is directed to a medical device for monitoring
the administration of drug to a patient by inhalation. In addition, the
invention includes systems and methods for treating patients,
particularly asthma patients, using remote monitoring of drug usage to
determine when an exacerbation is imminent.

BACKGROUND OF THE INVENTION

[0004]Over twenty million Americans suffer from asthma or chronic
obstructive pulmonary disease (COPD). These diseases are characterized by
periods of relative normalcy punctuated by acute attacks (exacerbations)
that may be severe enough to require hospitalization. Typically, an
attack is preceded by a progressive increase in a patient's use of
"rescue" medication to alleviate respiratory difficulties and a decrease
in lung function, as measured by peak expiratory flow rate. These changes
usually occur several days or weeks before an attack and can serve as a
signal for initiating preemptive treatment. Unfortunately, patients often
lack the time or resolve to keep accurate records of drug usage. As a
result, they may not become aware that their condition is deteriorating
until it is too late to prevent an attack requiring urgent medical
attention. Also, pediatric, elderly, or impaired patients may lack the
capacity for carefully monitoring changes in drug use patterns.

[0005]Many different types of inhalation devices have been developed and
used by respiratory patients for delivering a carefully controlled dosage
of medication (see, e.g., U.S. Pat. Nos. 6,223,746; and 6,532,955). Some
of these devices have microprocessors and sensors for counting the number
of doses administered (U.S. Pat. Nos. 6,138,669; and 5,593,390) or have
other adaptations to improve delivery characteristics (U.S. Pat. Nos.
5,477,849). However, most continue to rely upon patients to monitor their
own drug use patterns.

[0006]To the extent that devices that can be used to detect and monitor
patient self-administration of inhaled drugs have been described in the
prior art (e.g., WO01/024690; U.S. Pat. No. 5,363,842), they are
typically used to monitor patient compliance with physician instructions,
or to ensure that a patient receives no more than a certain dose of a
medication. Generally, there has not been a focus on monitoring inhaled
drug usage to recognize when a patient's condition is likely to be
deteriorating.

[0007]Moreover, in the existing devices, the mechanism for detecting that
a dose has been dispensed is usually within the device, often in a
position in which it can be easily fouled by dirt or accumulated
medication. The positioning of the detection mechanism often makes the
design of the devices relatively complex, and increases the possibility
of failure. Monitoring devices that are more robust and more compatible
with conventional types of inhalers would be beneficial.

SUMMARY OF THE INVENTION

[0008]Aspects of the present invention provide devices, systems, and
methods for monitoring patient inhaled drug usage to predict whether or
not an acute attack or exacerbation of a chronic disease or condition is
imminent. As one example, the disclosed devices, systems, and methods may
be particularly useful in the treatment of asthma.

[0009]One aspect of the invention provides an instrumented metered dose
inhaler with an inhaler portion and a sensor/transmitter portion. The
inhaler portion allows the patient to self-administer an inhaled dose of
a drug, such as a short-acting bronchodilator. The sensor/transmitter
portion, which is external to the inhaler portion, registers that a dose
has been dispensed and transmits that information wirelessly to a remote
station. In one embodiment, the inhaler portion may be coupled to the
sensor/transmitter portion by a simple mechanical coupling. For example,
in one embodiment, a cap or lip may be fitted to the inhaler's medication
canister, such that when the medication canister is depressed to dispense
a dose, the cap or lip depresses and actuates an electrical switch, thus
indicating that a dose has been dispensed. In some embodiments, the
sensor/transmitter portion may be easily added to a conventional inhaler,
allowing existing inhalers to be retrofit with instrumentation for
monitoring.

[0010]Another aspect of the invention relates to a system for predicting
disease exacerbations based on inhaled drug usage patterns. The system
comprises one or more instrumented metered dose inhalers described above
and a monitoring system. The monitoring system receives information
regarding dispensed doses from the one or more inhalers and associates
that information with patient records. Either or both of the inhalers and
the monitoring system may be adapted to analyze the information from the
inhalers to determine if any drug usage patterns indicate that an acute
attack or disease exacerbation is imminent.

[0011]Yet another aspect of the invention relates to methods for
predicting disease exacerbations based on inhaled drug usage patterns.
The methods involve collecting data on usage of a first inhaled
therapeutic agent by a patient essentially in real time as doses of the
first inhaled therapeutic agent are dispensed, for example, using an
instrumented metered-dose inhaler of the type described above, analyzing
the data, and notifying medical personnel if any drug usage patterns
indicate that an acute attack or disease exacerbation is imminent. In
some embodiments, a second therapeutic agent or another form of
intervention may be administered if an acute attack or disease
exacerbation is imminent. The second therapeutic agent may be an inhaled
corticosteroid, an oral corticosteroid, a leukotriene modifier, a long
acting beta2 agonist or a methylxanthine.

[0012]Other aspects, features, and advantages of the invention will be set
forth in the description that follows.

BRIEF DESCRIPTION OF THE DRAWINGS

[0013]The invention will be described with respect to the following
drawing figures, in which the same reference numerals will refer to the
same features throughout the figures, and in which:

[0014]FIG. 1 is a perspective view of an instrumented metered-dose inhaler
according to one embodiment of the invention;

[0015]FIGS. 2-3 are front and side elevational views, respectively, of the
inhaler of FIG. 1;

[0016]FIG. 4 is a top plan view of the inhaler of FIG. 1, with the
medication canister disconnected and shown separately;

[0017]FIG. 5 is a side elevational view of the inhaler similar to the view
of FIG. 3, illustrating the actuation of the device to dispense a dose of
the drug;

[0018]FIG. 6 is a perspective view of an alternate embodiment of the
inhaler, in which the sensor/transmitter portion of the device may be
attached to a conventional inhaler;

[0019]FIG. 7 is an illustration of a system for monitoring patient inhaled
medication usage and disease progression according to another embodiment
of the invention;

[0020]FIG. 8 is an illustration of a method for detecting and predicting
disease exacerbations according to yet another embodiment of the
invention; and

[0021]FIG. 9 is an illustration of another method for detecting and
predicting disease exacerbations.

DETAILED DESCRIPTION OF THE INVENTION

[0022]FIG. 1 is a perspective view of an instrumented metered-dose
inhaler, generally indicated at 10, according to one embodiment of the
invention. The metered-dose inhaler 10 includes an inhaler portion 12 and
a sensor/transmitter portion 14.

[0023]For the purposes of the present application, the term "metered dose
inhaler" will include both inhalers that deliver a liquid aerosol and dry
powder inhalers. The illustrated inhaler 10 is configured for a liquid
medication, such as albuterol, but other embodiments of the inhaler 10
may be configured for other types and sizes of inhalers.

[0024]The inhaler portion 12 of the illustrated embodiment is essentially
a standard, L-shaped inhaler with a medication reservoir compartment 15
for a medication reservoir or canister 16, and a mouthpiece 18 for
inhalation. Between the compartment 15 housing the medication canister 16
and the mouthpiece 18 is a flow pathway including a conventional flow
chamber (not shown in the figures) that disperses the medication and
mixes it with air as it is administered. FIG. 4 is a top plan view of the
inhaler 10 with the medication canister 16 removed from the compartment
15. The opening 20 to the flow pathway is visible in FIG. 4.

[0025]In embodiments of the invention, the inhaler portion 12 typically
has a movable part that moves between a dispensing position, in which the
inhaler portion 12 is actuated to dispense a dose of medication, and a
non-dispensing position, in which medication does not flow from the
medication reservoir compartment 15 to the mouthpiece 18. The movable
part is typically biased toward the non-dispensing position. The movement
of the moveable part may be linear, rotational, or of any other type. The
movable part is generally coupled to a valve or other structure that is
operable to release a flow of medication. In the illustrated embodiment,
the canister 16 acts as the movable part, although in other embodiments
of the invention, rods, levers, tabs, and hinged, rotatable portions may
all be used as moving parts.

[0026]The canister 16 is generally of a conventional type and typically
contains a supply of pressurized medication with a built-in valve. The
canister 16 is installed in its compartment 15 such that its nozzle 22
bears against the opening 20 to the flow chamber. When the canister 16 is
depressed downwardly, a dose of the drug is aerosolized and propelled
into the flow chamber, to be inhaled by the patient through the
mouthpiece 18. During the process of dispensing a dose, air may be drawn
into the inhaler portion 12 and mixed with the medication in the
conventional way. Other embodiments of the invention may use other types
of medication reservoirs and other methods of dispensing doses.

[0027]Generally speaking, if the patient's underlying condition is asthma,
the medication will be a bronchodilator, typically a short-acting
beta2 agonist, such as albuterol; bitolterol mesylate; levalbuterol;
metaproterenol sulfate; pirbuterol acetate; and terbutaline sulfate. As
will be described below in more detail, if it appears that a patient is
approaching an acute attack, there are several second drugs that may be
given in an attempt to avert it or reduce its severity. These include
long acting beta2 agonists (e.g., salmeterol; formoterol;
bambuterol); inhaled corticosteroids (e.g., beclomethasone; budesonide;
flunisolide; fluticasone; triamcinolone); leukotriene modifiers (e.g.,
montelukast; zafirlukast; zileuton); oral corticosteroids (e.g.,
prednisolone; prednisone; methylprednisolone); methylxanthines (e.g.,
theophyline); IgE inhibitors (e.g., omalizumab); cromolyn; and
nedocromil. These drugs have all been used or suggested for use for
asthmatics and dosages, duration of administration, and potential side
effects are well known in the art. They may be used in any
pharmaceutically acceptable form including any pharmaceutically
acceptable salt form. The same or different drugs may be used for other
conditions. Situations in which a second drug may be used will be
described below in more detail.

[0028]As was described above, the inhaler 10 also includes a
sensor/transmitter portion 14. As shown in FIGS. 1-4, the general
arrangement of the inhaler 10 is such that the inhaler portion 12 is
nested within and surrounded by the sensor/transmitter portion 14. One
purpose of the sensor/transmitter portion 14 is to sense that a dose of
medication has been dispensed and to communicate that fact to a remote
monitoring station.

[0029]Many of the components of the sensor/transmitter portion 14 are
contained within a housing 24, which may be plastic, metal, or some other
durable material that protects the components from damage. However,
protruding from the housing 24 and positioned so as to be adjacent but
external to the inhaler portion 12 is a dose-dispensing sensor 26. In the
illustrated embodiment, the dose-dispensing sensor 26 is essentially an
electrical switch in the form of a depressable button. When the
dose-dispensing sensor 26 is actuated (i.e., depressed), it establishes
an electrical signal indicating that a dose of medication has been
dispensed. The basic switch design is well known in the art and is
described fully in US 20050172958 (see especially FIGS. 3A and 3B). In
essence, the depression of the actuator moves a contact rod to a position
where the switch is closed to allow current flow. After compression, the
contact rod springs back to its original position opening the circuit and
preventing current flow.

[0030]The canister 16 is coupled to the dose-dispensing sensor 26 of the
illustrated embodiment by means of a cap or lip 28 that is sized to
accommodate the top end of the canister 16 and is releasably secured
thereto by means of one or more set screws 30. The cap or lip 28 is of
sufficient diameter to overhang the canister 16. Thus, as the canister 16
is depressed, the cap or lip 28 pushes down on and actuates the
dose-dispensing sensor 26. This simple mechanical coupling between the
canister 16 and the dose-dispensing sensor 26 is robust and simple to
use. However, in other embodiments, the dispensing of a dose may be
sensed by other means, including magnetic sensors (e.g., Hall Effect
sensors) and optical sensors.

[0031]The position of the dose-dispensing sensor 26 and the simple means
by which it is coupled to the canister 16 to sense when a dose has been
dispensed may have certain advantages. For example, an off-the-shelf
standard inhaler may be used as the inhaler portion 12 of the inhaler 10.
Additionally, the dose-dispensing sensor 26 is not within the flow
pathway, where it might be fouled by medication particles or droplets.
Moreover, the relatively large size of the components may make the
sensor/transmitter portion 14 easier to assemble, maintain, and repair.
Furthermore, in the event that the sensor/transmitter portion 14 should
fail, the arrangement of the inhaler 10 is such that the patient may
continue to dispense medication as normal; thus, mechanical or electrical
failure would not prevent a patient from getting his or her medication.

[0032]Also within the housing 24 and connected or coupled to the
dose-dispensing sensor 26 is a wireless transmitter 32, which is shown
schematically in the view of FIG. 3. The purpose of the wireless
transmitter 32 is to transmit a signal indicating that a dose of
medication has been administered to a remote monitoring station. (As will
be explained below in more detail, that signal may, and usually will,
contain additional information as well.)

[0033]The wireless transmitter 32 may be any sort of wireless transmitter
known in the art, provided that it provides the capability to transmit
from any place that the patient is likely to be. In the illustrated
embodiment, the wireless transmitter 32 may be a conventional GSM
cellular network transceiver, with associated components. In other
embodiments, the wireless transmitter 32 may be adapted to transmit using
substantially any frequency band or transmission protocols (e.g., CDMA,
WiFi, WiMax, etc.).

[0034]The sensor/transmitter portion 14 may also include storage (e.g.,
random access memory, read-only memory, flash memory), and a central
unit, such as a microprocessor, connected to the other components. An
input/output (I/O) controller and appropriate connection ports may also
be included in order to facilitate the process of programming the inhaler
10 or communicating with it at short range. Although not shown in the
illustrated embodiment, the sensor/transmitter portion 14 may also be
provided with a display screen, one or more indicator lights, or another
means for communicating its status to the user. Additionally, to the
extent desired, the sensor/transmitter portion 14 may also include one or
more user inputs. The components of the sensor/transmitter portion 14 may
be directly connected to one another, or data may be shared among the
components using a data bus or another similar arrangement. Generally,
the sensor/transmitter portion 14 would be powered by one or more
batteries, space for which is provided in the housing 24.

[0035]It will be realized that although a microprocessor is one type of
central unit that may be used in the sensor/transmitter portion 14 of the
inhaler 10, other types of devices may be used. For example, some or all
of the functions described here may be implemented in an
application-specific integrated circuit (ASIC). In general, any type of
device capable of performing the functions described in the present
application may be used.

[0036]As was noted above, the wireless transmitter 32, and many of the
other processing components of the sensor/transmitter portion 14, may be
conventional components from a cellular telephone. Cellular telephones,
or, to use a more general term, embedded devices, increasingly have the
performance and capabilities of general-purpose computers. For example,
U.S. Patent Application Publication No. 20060066731 illustrates a
cellular telephone/embedded device architecture with significant
processing power and most, if not all, of the functions of a
general-purpose computer. These sorts of components are readily
available, well known, and also provide the possibility for bidirectional
communication in some circumstances.

[0037]In a relatively simple embodiment, an electrical signal from the
dose-dispensing sensor 26 would be registered and recorded by the
microprocessor or other central unit. Since the inhaler 10 may be
actuated to dispense doses of medication several times in succession, a
transmission reporting the dose(s) would generally be sent some
predetermined amount of time after the last dose was administered. For
example, a transmission reporting the dose(s) may be sent one minute
after the last dose was dispensed. (In medical terms, a "dose" of a drug
may comprise more than one puff or inhalation from an inhaler; however,
the inhaler 10 would generally report in terms of the number of times
that puffs were dispensed, even though a dose may properly comprise two
or more puffs or actuations. Those units may be later be converted.)

[0038]The transmission itself may have any format or be encoded for
transmission in any manner. Depending on the embodiment, the
microprocessor or other central unit may add additional information to
the transmission, such as the date and time the dose(s) were dispensed,
and state information about the inhaler 10, such as the amount of battery
power remaining

[0039]Moreover, the inhaler 10 need not transmit only immediately after a
dose has been administered. For example, in some embodiments, it may be
advantageous to program the inhaler 10 to power up and transmit a signal
once a day, or at some other predetermined interval, to confirm that it
is still active and functional. In those embodiments, if an inhaler 10
fails to report in at its designated intervals, the patient may be
contacted to determine what his or her situation is.

[0040]As those of skill in the art will realize, it is advantageous to
have some means by which to identify each individual inhaler 10 if
multiple inhalers 10 are in use within the same system. There are several
ways in which that may be accomplished. In the illustrated embodiment,
the inhaler 10 communicates via a standard cellular telephone network and
therefore has a telephone number associated with it. Thus, any
communication from the inhaler 10 will have a unique telephone number
associated with it. In addition or alternatively, the microprocessor
could add a unique identifier, such as a serial number, to the outgoing
data transmission.

[0041]The inhaler 10 may also store a local copy of the dose
administration information, and may be configured and adapted to display
that information, either using output devices (e.g., a display screen or
indicator lights) provided as a part of the sensor/transmitter module 14
of the inhaler 10 or through an external display or device. Moreover,
should a transmission fail, the information may be stored for later
transmission when service once again becomes available.

[0042]The precise amount of storage space and computing power provided as
a part of the inhaler 10 and its sensor/transmitter portion 14 may
depend, at least in part, on the precise functions that the inhaler 10 is
tasked to perform. The above describes a relatively simple embodiment;
however, in some embodiments, pattern analysis, detection, and two-way
communication tasks may be performed in whole or in part by the inhaler
10.

[0043]The form of the inhaler may vary considerably from embodiment to
embodiment. For example, in the inhaler 10, the sensor/transmitter
portion 14 is essentially permanently attached to the inhaler portion 12.
In other embodiments, that may not be the case. For example, FIG. 6 is a
perspective view of an inhaler 100 according to another embodiment of the
invention. The inhaler 100 is substantially similar to the inhaler 10 of
FIGS. 1-5, and those parts not described in detail here may be assumed to
be the same or substantially the same; however, in the inhaler 100, the
sensor/transmitter portion 114 is releasably connected to the inhaler
portion 112 by way of semi-rigid plastic straps 116, such that the
sensor/transmitter portion 114 may be detached from the inhaler portion
112. This embodiment may be particularly useful in retrofitting existing
inhalers with a sensor/transmitter portion 114.

[0044]In some embodiments, the inhaler 10, 100 may be constructed and
arranged to contain a second therapeutic agent, as described above, to be
dispensed to the patient under certain conditions, particularly when a
disease exacerbation is detected. That second agent may be stored, for
example, in a separate medication reservoir for inhalation. If the second
therapeutic agent is in tablet or caplet form, it may be stored in a
compartment in the inhaler 10, 100. Depending on the embodiment, the
patient may be able to open that compartment at will, or it may open only
in response to a signal sent by a medical professional authorized to
dispense the drug. In further embodiments, the inhaler 10, 100 may be
programmed to dispense a mixed dose of two inhaled medications depending
on the patient's particular condition. Alternately, the patient may
simply be provided with instructions regarding how to titrate or
apportion the doses of the first and second therapeutic agents. In the
simplest embodiments, the patient may be provided with another inhaler or
other dispensing device for the second therapeutic agent. That inhaler
may or may not be an inhaler 10, 100 according to the present invention.

[0045]Instrumented metered-dose inhalers according to embodiments of the
present invention may be used simply to record when doses of a medication
are administered and to confirm that a patient is complying with
physician orders. However, such instrumented metered-dose inhalers are
most advantageously used not only to perform those basic tasks, but also
to predict, based on drug usage patterns, when an acute attack or
exacerbation is likely to occur.

[0046]Studies show that increased use of short-acting inhaled beta2
agonists among asthma patients is more common before an exacerbation and
before asthma-related death (Chan-Yeung, et al., Am. J. Respir. Crit.
Care Med. 154: 889-93 (1996); Hessel, et al., Ann. Allergy Asthma Immunol
83:362-368 (1999); Cairns, Clin. Chest Med. 27: 99-108 (2006)).
Prospectively, albuterol use of greater than 4 times a day was found to
have a relative risk of 1.33 for an exacerbation and nocturnal symptoms
had a relative risk of 1.79 (Gibson, et al., Ann. Intern. Med.
123:488-492 (1995)). Thus, both the amount of drug usage and the time of
usage may be important indicators of an impending exacerbation.
Exacerbations usually respond well to additional medication such as
corticosteroids and, if treatment is initiated early enough, it may be
possible to avert the attack or, at the least, reduce its severity.
Unfortunately, patients may not recognize warning signs either because
drug usage escalates gradually and they are preoccupied with other
matters or, in some cases, because their cognitive abilities are
impaired, e.g., due to age or illness.

[0047]Thus, aspects of the present invention provide systems and methods
for identifying exacerbation patterns--patterns of medication use that
would tend to indicate that a disease exacerbation, or another other form
of deterioration or complication, is imminent--and notifying both a
physician or other medical professional and the patient. Additionally, as
was noted briefly above, systems and methods according to embodiments of
the invention may provide for bi-directional (i.e., two-way)
communication with the patient for diagnostic or interventional purposes
when exacerbations or complications occur.

[0048]FIG. 7 is a schematic illustration of a system, generally indicated
at 200, according to one embodiment of the invention. In system 200, a
plurality of inhalers 10 are shown, each presumably belonging to a
different patient. It should be understood that although inhalers 10, 100
according to embodiments of the present invention are shown as a part of
system 200, other types of instrumented inhalers may be used for at least
some of the functions and tasks described with respect to system 200. If
the inhalers that are used as part of system 200 have additional features
not found in the inhalers 10, 100 described here, those features may be
taken advantage of. For example, data from the flowmeter of the inhaler
disclosed in US 20050172958 may be taken into account in determining
whether or not an exacerbation pattern exists.

[0049]Each of the inhalers 10, 100 communicates wirelessly with a remote
transceiver 202. In some embodiments, that remote transceiver 202 may be
a cell or base station in a cellular telephone network.

[0050]The remote transceiver 202 is in communication with a monitoring
system 204. Although not shown in FIG. 7, the remote transceiver 202
would generally be connected to a communications network of its own, and
may communicate with the monitoring system 204 indirectly through a
number of intermediary systems and elements. For example, traffic from
the remote transceiver 202 may pass through the proprietary network of a
cellular communications network and through a gateway to the Internet,
through which it reaches the monitoring system 204.

[0051]The monitoring system 204 itself is a system, or a plurality of
interconnected, interoperating systems, that are charged with monitoring
the transmissions from the inhalers 10, 100, performing predictive
analysis to determine when patients are experiencing exacerbation
patterns that might be indicative of forthcoming exacerbations or
complications, and distributing notifications regarding patient status to
the appropriate decision making or disease-management medical personnel.
The monitoring system 204 also keeps the primary set of records
associated with the system 200 and, for example, would usually be
programmed with a database that is capable of associating incoming
traffic from particular inhalers with patient information, including the
patient's name, physician or other attending medical professional,
contact information for the patient and relevant medical professionals,
pertinent medical history, name of the patient's preferred pharmacy, and
any other information deemed relevant. The database may, for example, be
indexed by the cellular telephone number of the patient's inhaler 10,
100, or by some other kind of unique identifier assigned to the patient
or his or her inhaler 10, 100.

[0052]The monitoring system 204 communicates through a communications
network 206 to notification devices 210 associated with the physicians or
other medical professionals 208 attending the patients. The notification
devices 210 may be cellular telephones, pagers, alphanumeric pagers,
personal digital assistants, smartphones, computers, or any other kind of
device or system capable of receiving notification messages directly or
indirectly from the monitoring system 204 and providing the medical
professionals 208 with those notifications. Depending on the situation,
particularly if there are relatively few inhalers 10, 100 to be
monitored, one of the notification devices 210 could also serve as the
monitoring system 204.

[0053]The type of notification that is sent will depend on the types of
notification devices 210 that are in use, as well as the preferences of
the individuals using the system. As one example, the monitoring system
204 may send e-mails to the attending physicians, disease management
nurses, or other responsible medical professionals detailing the
condition of each patient and whether or not that patient is likely to be
experiencing an exacerbation pattern, either on a regular basis (e.g.,
daily), when a pattern requiring immediate notification is detected, or
both. This will be described below in more detail.

[0054]In some embodiments, the monitoring system 204 may also be used to
convey messages or instructions back to the inhalers 10, 100 and the
respective patients. For example, as was described above, in some
embodiments, the patient may be instructed to take a second therapeutic
agent to manage an exacerbation or avert an impeding exacerbation. Those
instructions could come from or through the monitoring system 204.
Additionally, the monitoring system 204 could, if the inhalers 10, 100
are appropriately equipped with a display and input mechanism, send
questionnaires or other queries for the users to answer, in order to
assess whether or not the pattern detected by the monitoring system 204
is corroborated by other signs or symptoms. For example, patients could
be asked to take an asthma questionnaire, in which case the questions may
be sent by the monitoring system 204 to the inhaler 10, 100 of the
patient in question. Alternatively, appropriate questionnaires and other
contingency protocols and instructions may be stored in the inhalers 10,
100 and activated by a communication from the monitoring system 204.

[0055]In describing the elements and functions of system 200, it may thus
be said that the inhalers 10, 100 transmit their data to a remote
station, that data is processed, and appropriate notifications are made
if the patient's condition or pattern of medication usage so warrants.
However, the term "remote station" is a general one, and may encompass
any one of or all of the elements 202, 204, 210 that receive and process
signals from the inhalers 10, 100. The precise nature of the elements
that receive and process signals from the inhalers 10, 100 may vary from
embodiment to embodiment; the illustration of FIG. 7 is but one example.
Those of skill in the art will also realize that although certain tasks
and capabilities have been ascribed to certain elements of system 200, as
a practical matter, at least some functions of system 200 may be equally
well performed by a number of elements in system 200. For example, some
of the tasks ascribed to the monitoring system 204, such as the detection
of exacerbation patterns, may be equally well performed by the inhalers
10, 100 themselves in some embodiments.

[0056]As was noted above, one function of system 200 is to detect
exacerbation patterns. The description above points out two such specific
exacerbation patterns for albuterol: use greater than 4 times a day, and
nocturnal use of the drug when the patient in question would normally be
sleeping. More generally, exacerbation patterns may involve any or all of
the following: increased frequency of use (e.g., more actuations per 24
hour period or per 72 hour moving window); increased nocturnal frequency
(e.g., between 10 PM and 6 AM) in a patient who would normally be
sleeping; and increased stacking of doses (e.g., more than two successive
actuations in less than 10 minutes). Additionally, seasonal usage may be
taken into account. For example, a patient's usage on a weekly basis may
be determined, seasons during which the patient tends to experience
exacerbations could be identified, and interventions may be planned for
the next season.

[0057]Although absolute thresholds may be used in determining whether or
not a particular patient is experiencing an exacerbation pattern, it may
be more advantageous to establish which usage patterns qualify as
exacerbation patterns for each individual patient. That could be done,
for example, by tracking the patient's usage prior to a known
exacerbation (e.g., an emergency room or physician visit for acute
treatment) and using that data to establish what usage patterns qualify
as exacerbation patterns. In some embodiments, the inhalers 10, 100 may
auto-calibrate (or be calibrated by the monitoring system 204) for the
patient's baseline drug usage by averaging the patient's drug usage over
a defined period of time, and defining an exacerbation pattern to be any
pattern that deviates from the average by more than a certain amount. As
an example, an increase in the frequency of administration of a short
acting beta2 agonist of 20-100% measured over a period of 3 to 10
days would generally be considered an exacerbation pattern, and may also
be grounds for administering the second therapeutic agent, as described
above.

[0058]The above gives a broad overview of the types of exacerbation
patterns that may be detected. However, not all exacerbation patterns are
necessarily equally well correlated to disease exacerbations; some
exacerbation patterns may be more strongly indicative of an impending
exacerbation, and some exacerbation patterns may be indicative of a more
severe exacerbation. Systems and methods according to embodiments of the
present invention may take these differences into account.

[0059]FIGS. 8 and 9 are flow diagrams illustrating two similar methods of
detecting and predicting disease exacerbations according to embodiments
of the invention. Method 300 of FIG. 8 illustrates a scenario in which
the inhaler 10, 100 does not have significant processing capabilities,
and thus, does not perform any pattern analysis tasks. Method 400 of FIG.
9 illustrates an opposite scenario in which the inhaler 10, 100 does have
significant processing power. As those of skill in the art will realize,
methods 300 and 400 represent opposite ends of a spectrum, and methods
according to embodiments of the invention may apportion functions or
tasks to different components of the system in many different ways.
Moreover, both methods illustrate only routine cycles of use; other
calibration, reporting, and interactive tasks, particularly those
described above, may be included in the methods.

[0060]Method 300 begins at 302 and continues with task 304, in which the
inhaler 10, 100 detects whether or not a dose of medication has been
administered. If a dose has been administered (task 306:YES), method 300
continues with task 308; if a dose has not been administered (task
306:NO), method 300 returns to task 304. The inhaler 10, 100 may remain
in this loop for a long period of time, and may be programmed to power
down into a "standby" or "sleep" mode accordingly, shutting down the
transmitter or other components until needed in order to conserve power.

[0061]When a dose has been administered (task 306:YES), the inhaler 10,
100 powers up and transmits an appropriate report to its remote station,
as described above. Typically, that report would reach the monitoring
system 204, which would timestamp and store the information in its
database before proceeding with task 310, in which the patient's usage
patterns are tracked and analyzed to determine whether an exacerbation
pattern exists.

[0062]In determining whether an exacerbation pattern exists, any of the
criteria or methods described above may be employed, and any other
medically reasonable criteria may also be employed. Other criteria may be
found in the literature. More generally, additional guidance regarding
patient monitoring and monitoring systems may be found in Tovar et al.
(Ann. Pharmacother. 38(1):126-133 (2004)); Marosi et al. (J. Asthma
38(8):681-690 (2001)); Martin et al. (J. Allergy Clin. Immumol. 103(3 Pt.
1):535-536 (1999)) and, especially US 20050172958.

[0063]Task 310 need not always be performed every time incoming data is
received. Rather, it may be delayed or performed on a regular schedule
(e.g., every 4-6 hours, every day, etc.). However, the more often task
310 is performed, the more likely it is that an exacerbation pattern will
be detected quickly if present, and the more likely it will be that the
patient receives timely intervention. Method 300 continues with task 312,
a decision task.

[0064]If no exacerbation pattern is detected (task 312:NO), the monitoring
system 204 may simply wait for the next packet of incoming data from an
inhaler 10, 100. In terms of FIG. 8, method 300 returns to task 304. If
an exacerbation pattern is detected (task 312:YES), method 300 continues
with task 314, in which appropriate notifications (e.g., by e-mail to a
physician or disease management nurse) are made.

[0065]As shown in FIG. 7, illustrating system 200, many inhalers 10, 100
may be in the field at any one time, and many may be in communication
with the monitoring system 204 at any one time. Thus, method 300 may be
executed may times concurrently or in parallel. If method 300 is executed
multiple times and several patients have exacerbation patterns for which
notifications are to be sent to the same physician or other destination,
the notifications may be concatenated to the extent practicable. If
multiple patients are covered by a single notification, their situations
may prioritized so that the most serious or potentially serious condition
is most readily seen. Patients whose usage is normal may also be included
in the notifications, for the sake of completeness. For example, a
physician may receive an e-mail similar to the following:

[0066]Although e-mail is given as one specific example of a mode of
notification, notifications may also be posted to a public or private
World Wide Web site, entered directly into an electronic medical records
system, or delivered in any other convenient fashion. Additionally, a
notification signal may be sent back to the inhaler 10, 100, in order to
notify the patient that a possible problem has been detected. Method 300
terminates at task 316.

[0067]Method 400 of FIG. 9 is similar in many respects to method 300, and
the description of method 300 above is thus applicable to method 400
unless otherwise indicated. Method 400 begins at task 402 and continues
with tasks 404 and 406, which are substantially similar to tasks 304 and
306 of method 300.

[0068]However, in method 400, if a dose has been administered (task
406:YES), method 400 continues with task 408, in which the patient's
usage pattern is analyzed. As was described above, in method 400, the
inhaler 10, 100 is assumed to have substantial processing power, and thus
performs at least some analysis tasks. Task 408 of method 400 generally
corresponds with task 310 of method 300, although the inhaler 10, 100 may
perform only a portion of the "full" analysis, depending on its
capabilities.

[0069]Following task 408, method 400 continues with task 410, a decision
task. In task 410, if an exacerbation pattern is detected (task 410:YES),
method 400 continues with task 412; if not (task 410:NO), method 400 may
return to task 404. (It should be noted that the inhaler 10, 100 will
report that a dose has been administered regardless of whether or not an
exacerbation pattern was detected in most embodiments. In those
embodiments, it may be desirable or advantageous to report that no
exacerbation pattern was detected in order to save time and processing
power on the monitoring system 204. However, in other embodiments, the
monitoring system 204 may confirm the results reached by the inhaler 10,
100 regardless of the outcome of task 408.)

[0070]Tasks 412 is somewhat similar to task 308 of method 300; the inhaler
10, 100 reports to the monitoring system 204. However, in task 412, the
inhaler 10, 100 may also report the results of any analysis that was
performed, in addition to the bare fact that a dose was dispensed. Method
400 continues with task 414, which is essentially the same task task 314
of method 300, and terminates and returns at task 416.

[0071]Any method according to an embodiment of the present invention may
be encapsulated in one or more sets of machine-readable instructions that
are interoperable with a machine or machines to perform the tasks of the
method. Machine-readable media include magnetic and optical media, as
well as FLASH drives, read-only memory, and any other sort of
machine-readable storage medium known in the art.

[0072]As was described above, devices, systems, and methods according to
embodiments of the invention will be of particular use to patients with
respiratory diseases, such as asthma and chronic obstructive pulmonary
disease. However they may also be used for patients with cystic fibrosis,
non-cystic fibrosis bronchiectasis, forms of interstitial lung disease,
reactive airways disease, occupational lung disease, congestive heart
failure, and in patients that have received a solid organ transplant or
bone marrow transplant.

[0073]All references cited herein are fully incorporated by reference.
Having now fully described the invention, it will be understood by one of
skill in the art that the invention may be performed with a wide range of
modifications and changes and under a broad range of conditions, without
affecting the spirit or scope of the invention or any embodiment thereof.